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Oxytocin and prolactin release after electroconvulsive therapy: a pilot study
CURRENT THERAPEUTIC RESEARCH’ VOL. 56, NO. 3, MARCH 1995
OXYTOCIN AND PROLACTIN RELEASE AFTER ELECTROCONVULSIVE THERAPY: A PILOT STUDY M.
DHYANNE WARNER,’NELSONGRUBER,2AND CECILIA A. PEABODY’
‘Department of Psychiatry, Stanford University Medical School, Stcmnford,California, 2Department of Psychiatry, University of Texas Medical School, Houston, Teras, and 3Vetemns Administration Hospital, Menlo Park, California
ABSTRACT This pilot study was conducted to confirm earlier reports of increased prolactin and oxytocin levels after seizures induced by electroconvulsive therapy (ECT). Blood was drawn at 5, 10, 15, 30, and 60 minutes post-seizure from seven psychiatric inpatients with major depressive disorder or mixed bipolar disorder who underwent ECT as part of their clinical treatment. There was a significant increase in prolactin levels at 15 minutes and oxytocin levels at 5 minutes compared with the levels at 66 minutes. These hormone elevations in such a small sample size attest to the robustness of our findings. INTRODUCTION
Several investigators have measured neuroendocrine parameters after seizures induced by electroconvulsive therapy (ECT), partly in an attempt to determine the underlying mechanism of action of ECT in the treatment of patients with depression. Rapid increases in plasma concentrations of neurophysins, vasopressin, oxytocin, prolactin, adrenocorticotropic hormone, cortisol, and luteinizing hormone have been reported after ECT.lm7 Prolactin has been the most consistently documented hormone shown to increase, with peak levels at 15 minutes after ECT-induced seizures.5p718 Only two studies have investigated oxytocin, with one study reporting a peak at 5 minutes post-seizure. 6pgIn our pilot study, we attempted to replicate the findings of increased prolactin and oxytocin levels after ECTinduced seizures. PATIENTSAND METHODS
The study protocol was approved by the University of Texas Health Science Center’s Committee for the Protection of Human Subjects. Seven psychiatric inpatients (three men and four women) with a mean age of 33.4 Address correspondence to: Cecilia Peabody, MD, % VA Hospital at Menlo Park, 795 Willow Bd, Building 324-E103, Menlo Park, CA 94025. Received forpublicationon December 6.1994. Printed in the U.S.A. Beproduction in whole or part is not permitted.
226
call-393xmM3.50
M. D. WARNER
ET AL.
years (range, 21 to 50 years) were included in the study. Five patients had major depressive disorder and two mixed bipolar disorder, diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders (third edition, revised). The protocol was explained to each patient, and informed consent was obtained. All patients were withdrawn from psychotropic medications for a minimum of 1 week before ECT. Patients had undergone three to nine ECT sessions at the time of assessment. The bifrontotemporal electrode position was used in all patients except one, who was treated using a unilateral nondominant D’Elia placement. Treatments were performed with a Thymatron unit (Somatics, Inc., Lake Bluff, Illinois). This device delivers a constant current (0.9 A) using a pulsed, bidirectional, square-wave stimulus with a pulse width of 1 ms and a frequency of 70 Hz; the maximum charge deliverable is 504 mC. Seizure duration was determined using the “cuff’ method; timing began with the first tonic movements noted after stimulus delivery and continued until the last clonic movement in the body stopped. The minimum seizure duration was 23 seconds and the maximum 53 seconds. Treatment medications were given intravenously. All patients received glycopyrrolate (0.2 mg) to protect against parasympathetic effects, methohexital sodium (about 1 mg/kg) to promote unconsciousness, and succinylcholine chloride (about 1 mgikg) to produce paralysis. Additionally, 5 of the 7 patients received labetalol hydrochloride (5 to 10 mg) to reduce their sympathetic response and 2 received tubocurarine chloride (3 mg) as a defasciculating agent. Appropriate ventilatory assistance was provided throughout the procedure with 100% oxygen. Blood was drawn at 5, 10, 15, 30, and 60 minutes after the ECTinduced seizure via an indwelling forearm catheter. Serum was collected for prolactin samples and plasma for oxytocin samples. All samples were centrifuged after the blood was drawn and stored at - 70 “C until assayed. The Nichols Institute in San Juan Capistrano, California assayed the oxytocin samples in the same batch. Dr. David Lawson’s laboratory at Wayne State University in Detroit, Michigan assayed the prolactin samples in the same batch. The intraassay coefficient of variation for both hormones was less than 10%. RESULTS
The effects of ECT on blood prolactin and oxytocin concentrations are shown in the table. There was a significant increase in prolactin at 15 minutes compared with 60 minutes using a paired t test (P < 0.005). There also was a significant increase in oxytocin at 5 minutes compared with 60 minutes using a paired t test (P < 0.01). The 15-minute value for prolactin was missing for one patient so the lo-minute value was substituted. Similarly, a 60-minute prolactin value was missing for another patient and the 227
OXYTOCIN
AND PROLACTIN
RELEASE
AFTER
ECT
Table. Prolactin (ng/mL) and oxytocin (pg/mL) concentrations (mean f SD) after seizures induced by electroconvulsive therapy (ECT). Time After ECT-induced Seizure (mln) 5
10
15
19.9 + 12.9 3.7 f 2.7$
39.6 f 15 2.1 k 1.2
4Y.T f ;T64t
+
30 3;:;
_’ ;52
+
60 7.6 f 5.4 0.6 f 0.6
* Not all atients had enou h blood drawn to be included in the analysis. t P < 0.105 compared wit fl 60 mmutes. t P < 0.01 compared with 60 minutes.
30-minute value was substituted. A third patient was missing a 60-minute value for oxytocin and the l&minute value was substituted. Both this patient and one other patient had a missing 30-minute oxytocin value. No other values were missing for either hormone. DISCUSSION AND CONCLUSION
Our finding of a peak prolactin level occurring 15 minutes after ECTinduced seizures is consistent with previous studies.197,8v10*11 Increased prolactin release has also been reported with bilateral electrode placement 12,13longer seizure duration,’ and after the first rather than repeated ECT \essions.7,10,14Almost as many investigators have failed to find increased prolactin release associated with any of these factors, such as bilateral electrode placement,7 longer seizure duration,” or repeat ECT sessions affecting prolactin values. ‘s8,11Our study did not address these additional factors because all patients but one received bilateral electrode placement, each patient was assessed at a different ECT session, and the sample size was too small to correlate seizure duration with prolactin release. In our patients, oxytocin concentrations peaked 5 minutes after the ECT seizure. This finding is consistent with data from Smith et a1.6 Only two previous investigators have measured radioimmunoassay oxytocin levels after ECT-induced seizures. Smith et al6 noted a lo-fold increase from baseline in 11 depressed patients within 5 minutes after a seizure and a decrease toward baseline values at 15 to 30 minutes. Devanand et al9 reported “large increases acutely” in oxytocin levels in 27 patients, but hormone values and times were not given. Furthermore, these investigators reported significantly greater oxytocin release with bilateral electrode placement. Studies by Scott et a13-5 and Whalley et al’ indirectly assessed oxytocin release by measuring its associated carrier peptide, a neurophysin (hNpI1). These authors reported an immediate surge of oxytocinassociated neurophysin, peaking at 5 to 6 minutes after the ECT-induced seizure. Scott et a14*5also noted that patients with good clinical outcomes
M.D.WARNERETAL
as assessed using depression rating scales had greater oxytocin-associated neurophysin release over baseline levels after their first ECT treatment compared with patients with poor clinical outcomes. In summary, our pilot study replicated earlier findings of prolactin and oxytocin levels peaking at 15 and 5 minutes, respectively, after an ECT-induced seizure. While the prolactin finding has been widely reported, only two previous studies have reported an oxytocin surge as measured by radioimmunoassay. 5*gOur findings of elevated prolactin and oxytocin levels with small sample sizes of 6 and 5 evaluable patients, respectively, attest to the robustness of these results. The clinical significance of these findings is unknown.
Acknouhdgment This work was performed at the University of Texas Medical School, Houston, Texas. References: 1. Whalley LJ, Dick H, Watts AG, et al. Immediate increases in plasma prolaotin and neurophysin but not other hormones after electroconvulsive therapy. Lancet. 1982;2: 1064-1068. 2. Whalley I.J, Eagles JM, Bowler GMR, et al. Selective effects of ECT on hypothalamic pituitary activity. Psycho1 Med. 1987;17:312-328. 3. Scott AIF, Whalley LJ, Bennie J, Bowler G. Oestrogen-stimulated neurophysin and outoome after electroconvulsive therapy. Lancet. 1986;1:1411-1414. 4. Scott AIF, Whalley LJ, Legros JJ. Treatment outcome, seizure duration and the neurophysin response to ECT. Biol Psychiatry. 1989;25:585-597. 5. Scott AIF, Shering A, Legros JJ, Whalley LI. Improvement in depressive illness is not associated with altered release of neurophysins over a course of ECT. Psychiatry Res. 1991;36:65-73. 6. Smith JE, Williams K, Burkett S, Glue P. Oxytocin and vasopressin responses to ECT. Psychiatry Res. 1990;32:201-202. 7. Kronfol Z, Hamdan-Allen G, Goel K, Hill EM. Effecta of single and repeated eleotrooonvulsive therapy sessions on plasma ACTH, prolactin, growth hormone, and oortisol concentrations. Peychmeuroendowinology. 1991;16:345-352. 8. Haskett RF, Zis AP, Albala AA. Hormone response to repeated electroconvulsive therapy: Effects of naloxone. Biol Psychiatry. 1985;20:623-633. 9. Devanand DP, Lo ES, Sackheim HA, et al. Specificity of ECT treatment parameters on plasma vaeopressin and oxytocin. Presented at the Annual Meeting of the Society for Biological Psychiatry, Montreal, Canada, May 1988. Abstract #226. 10. Aperia B, Thoren M, Wetterberg L. Prolaotin and thyrotropin in serum during electroconvulsive therapy in patients with major depressive illness. Acta Psych&r Scund. 1985; 72~302-308.
OXYTOCIN
AND PROLACTIN
RELEASE
AFTER
ECT
11. Scott AIF, Gow SM, Garden W, et al. Repeated ECT and prolactin release in depressed patients. Biol Psychiatry. 1992;31:613-616. 12. Swarts C, Abrams R. Prolactin levels after bilateral and unilateral ECT. Br J Psychiatry. 1964;144:643-645. 13. Papalcostas Y, Stephanis C, Markianos M, Papadimatriou G. Electrode placement and prolactin response to electroconvulsive therapy. Convubive Ther. 1986;2:99-107. 14. Deakin JFW, Ferrier IN, Crow TJ, et al. Effects of ECT on pituitary hormone release: Relationship to seizure, clinical variables and outcome. Br J Psychiatry. 1983;143:618624.
230
OXYTOCIN AND PROLACTIN RELEASE AFTER ELECTROCONVULSIVE THERAPY: A PILOT STUDY M.
DHYANNE WARNER,’NELSONGRUBER,2AND CECILIA A. PEABODY’
‘Department of Psychiatry, Stanford University Medical School, Stcmnford,California, 2Department of Psychiatry, University of Texas Medical School, Houston, Teras, and 3Vetemns Administration Hospital, Menlo Park, California
ABSTRACT This pilot study was conducted to confirm earlier reports of increased prolactin and oxytocin levels after seizures induced by electroconvulsive therapy (ECT). Blood was drawn at 5, 10, 15, 30, and 60 minutes post-seizure from seven psychiatric inpatients with major depressive disorder or mixed bipolar disorder who underwent ECT as part of their clinical treatment. There was a significant increase in prolactin levels at 15 minutes and oxytocin levels at 5 minutes compared with the levels at 66 minutes. These hormone elevations in such a small sample size attest to the robustness of our findings. INTRODUCTION
Several investigators have measured neuroendocrine parameters after seizures induced by electroconvulsive therapy (ECT), partly in an attempt to determine the underlying mechanism of action of ECT in the treatment of patients with depression. Rapid increases in plasma concentrations of neurophysins, vasopressin, oxytocin, prolactin, adrenocorticotropic hormone, cortisol, and luteinizing hormone have been reported after ECT.lm7 Prolactin has been the most consistently documented hormone shown to increase, with peak levels at 15 minutes after ECT-induced seizures.5p718 Only two studies have investigated oxytocin, with one study reporting a peak at 5 minutes post-seizure. 6pgIn our pilot study, we attempted to replicate the findings of increased prolactin and oxytocin levels after ECTinduced seizures. PATIENTSAND METHODS
The study protocol was approved by the University of Texas Health Science Center’s Committee for the Protection of Human Subjects. Seven psychiatric inpatients (three men and four women) with a mean age of 33.4 Address correspondence to: Cecilia Peabody, MD, % VA Hospital at Menlo Park, 795 Willow Bd, Building 324-E103, Menlo Park, CA 94025. Received forpublicationon December 6.1994. Printed in the U.S.A. Beproduction in whole or part is not permitted.
226
call-393xmM3.50
M. D. WARNER
ET AL.
years (range, 21 to 50 years) were included in the study. Five patients had major depressive disorder and two mixed bipolar disorder, diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders (third edition, revised). The protocol was explained to each patient, and informed consent was obtained. All patients were withdrawn from psychotropic medications for a minimum of 1 week before ECT. Patients had undergone three to nine ECT sessions at the time of assessment. The bifrontotemporal electrode position was used in all patients except one, who was treated using a unilateral nondominant D’Elia placement. Treatments were performed with a Thymatron unit (Somatics, Inc., Lake Bluff, Illinois). This device delivers a constant current (0.9 A) using a pulsed, bidirectional, square-wave stimulus with a pulse width of 1 ms and a frequency of 70 Hz; the maximum charge deliverable is 504 mC. Seizure duration was determined using the “cuff’ method; timing began with the first tonic movements noted after stimulus delivery and continued until the last clonic movement in the body stopped. The minimum seizure duration was 23 seconds and the maximum 53 seconds. Treatment medications were given intravenously. All patients received glycopyrrolate (0.2 mg) to protect against parasympathetic effects, methohexital sodium (about 1 mg/kg) to promote unconsciousness, and succinylcholine chloride (about 1 mgikg) to produce paralysis. Additionally, 5 of the 7 patients received labetalol hydrochloride (5 to 10 mg) to reduce their sympathetic response and 2 received tubocurarine chloride (3 mg) as a defasciculating agent. Appropriate ventilatory assistance was provided throughout the procedure with 100% oxygen. Blood was drawn at 5, 10, 15, 30, and 60 minutes after the ECTinduced seizure via an indwelling forearm catheter. Serum was collected for prolactin samples and plasma for oxytocin samples. All samples were centrifuged after the blood was drawn and stored at - 70 “C until assayed. The Nichols Institute in San Juan Capistrano, California assayed the oxytocin samples in the same batch. Dr. David Lawson’s laboratory at Wayne State University in Detroit, Michigan assayed the prolactin samples in the same batch. The intraassay coefficient of variation for both hormones was less than 10%. RESULTS
The effects of ECT on blood prolactin and oxytocin concentrations are shown in the table. There was a significant increase in prolactin at 15 minutes compared with 60 minutes using a paired t test (P < 0.005). There also was a significant increase in oxytocin at 5 minutes compared with 60 minutes using a paired t test (P < 0.01). The 15-minute value for prolactin was missing for one patient so the lo-minute value was substituted. Similarly, a 60-minute prolactin value was missing for another patient and the 227
OXYTOCIN
AND PROLACTIN
RELEASE
AFTER
ECT
Table. Prolactin (ng/mL) and oxytocin (pg/mL) concentrations (mean f SD) after seizures induced by electroconvulsive therapy (ECT). Time After ECT-induced Seizure (mln) 5
10
15
19.9 + 12.9 3.7 f 2.7$
39.6 f 15 2.1 k 1.2
4Y.T f ;T64t
+
30 3;:;
_’ ;52
+
60 7.6 f 5.4 0.6 f 0.6
* Not all atients had enou h blood drawn to be included in the analysis. t P < 0.105 compared wit fl 60 mmutes. t P < 0.01 compared with 60 minutes.
30-minute value was substituted. A third patient was missing a 60-minute value for oxytocin and the l&minute value was substituted. Both this patient and one other patient had a missing 30-minute oxytocin value. No other values were missing for either hormone. DISCUSSION AND CONCLUSION
Our finding of a peak prolactin level occurring 15 minutes after ECTinduced seizures is consistent with previous studies.197,8v10*11 Increased prolactin release has also been reported with bilateral electrode placement 12,13longer seizure duration,’ and after the first rather than repeated ECT \essions.7,10,14Almost as many investigators have failed to find increased prolactin release associated with any of these factors, such as bilateral electrode placement,7 longer seizure duration,” or repeat ECT sessions affecting prolactin values. ‘s8,11Our study did not address these additional factors because all patients but one received bilateral electrode placement, each patient was assessed at a different ECT session, and the sample size was too small to correlate seizure duration with prolactin release. In our patients, oxytocin concentrations peaked 5 minutes after the ECT seizure. This finding is consistent with data from Smith et a1.6 Only two previous investigators have measured radioimmunoassay oxytocin levels after ECT-induced seizures. Smith et al6 noted a lo-fold increase from baseline in 11 depressed patients within 5 minutes after a seizure and a decrease toward baseline values at 15 to 30 minutes. Devanand et al9 reported “large increases acutely” in oxytocin levels in 27 patients, but hormone values and times were not given. Furthermore, these investigators reported significantly greater oxytocin release with bilateral electrode placement. Studies by Scott et a13-5 and Whalley et al’ indirectly assessed oxytocin release by measuring its associated carrier peptide, a neurophysin (hNpI1). These authors reported an immediate surge of oxytocinassociated neurophysin, peaking at 5 to 6 minutes after the ECT-induced seizure. Scott et a14*5also noted that patients with good clinical outcomes
M.D.WARNERETAL
as assessed using depression rating scales had greater oxytocin-associated neurophysin release over baseline levels after their first ECT treatment compared with patients with poor clinical outcomes. In summary, our pilot study replicated earlier findings of prolactin and oxytocin levels peaking at 15 and 5 minutes, respectively, after an ECT-induced seizure. While the prolactin finding has been widely reported, only two previous studies have reported an oxytocin surge as measured by radioimmunoassay. 5*gOur findings of elevated prolactin and oxytocin levels with small sample sizes of 6 and 5 evaluable patients, respectively, attest to the robustness of these results. The clinical significance of these findings is unknown.
Acknouhdgment This work was performed at the University of Texas Medical School, Houston, Texas. References: 1. Whalley LJ, Dick H, Watts AG, et al. Immediate increases in plasma prolaotin and neurophysin but not other hormones after electroconvulsive therapy. Lancet. 1982;2: 1064-1068. 2. Whalley I.J, Eagles JM, Bowler GMR, et al. Selective effects of ECT on hypothalamic pituitary activity. Psycho1 Med. 1987;17:312-328. 3. Scott AIF, Whalley LJ, Bennie J, Bowler G. Oestrogen-stimulated neurophysin and outoome after electroconvulsive therapy. Lancet. 1986;1:1411-1414. 4. Scott AIF, Whalley LJ, Legros JJ. Treatment outcome, seizure duration and the neurophysin response to ECT. Biol Psychiatry. 1989;25:585-597. 5. Scott AIF, Shering A, Legros JJ, Whalley LI. Improvement in depressive illness is not associated with altered release of neurophysins over a course of ECT. Psychiatry Res. 1991;36:65-73. 6. Smith JE, Williams K, Burkett S, Glue P. Oxytocin and vasopressin responses to ECT. Psychiatry Res. 1990;32:201-202. 7. Kronfol Z, Hamdan-Allen G, Goel K, Hill EM. Effecta of single and repeated eleotrooonvulsive therapy sessions on plasma ACTH, prolactin, growth hormone, and oortisol concentrations. Peychmeuroendowinology. 1991;16:345-352. 8. Haskett RF, Zis AP, Albala AA. Hormone response to repeated electroconvulsive therapy: Effects of naloxone. Biol Psychiatry. 1985;20:623-633. 9. Devanand DP, Lo ES, Sackheim HA, et al. Specificity of ECT treatment parameters on plasma vaeopressin and oxytocin. Presented at the Annual Meeting of the Society for Biological Psychiatry, Montreal, Canada, May 1988. Abstract #226. 10. Aperia B, Thoren M, Wetterberg L. Prolaotin and thyrotropin in serum during electroconvulsive therapy in patients with major depressive illness. Acta Psych&r Scund. 1985; 72~302-308.
OXYTOCIN
AND PROLACTIN
RELEASE
AFTER
ECT
11. Scott AIF, Gow SM, Garden W, et al. Repeated ECT and prolactin release in depressed patients. Biol Psychiatry. 1992;31:613-616. 12. Swarts C, Abrams R. Prolactin levels after bilateral and unilateral ECT. Br J Psychiatry. 1964;144:643-645. 13. Papalcostas Y, Stephanis C, Markianos M, Papadimatriou G. Electrode placement and prolactin response to electroconvulsive therapy. Convubive Ther. 1986;2:99-107. 14. Deakin JFW, Ferrier IN, Crow TJ, et al. Effects of ECT on pituitary hormone release: Relationship to seizure, clinical variables and outcome. Br J Psychiatry. 1983;143:618624.
230